Study of ecdysterone metabolites isolated from rat urine

Abstract

547.926Metabolites of ecdysterone have been isolated from rat urine. By a combination of electron-impact and secondary-ion mass spectrometries and with the aid of accurate measurements of ion masses the molecular masses have been determined and structures have been proposed for three new metabolites, a common feature of which is the reduction of C~O to a methylene group. Ecdysterone metabolite (2) has the structure Steroids form one of the most important groups of organic compounds. Among the various metabolites produced by plants a not unimportant place is occupied ecdysteroids found in animals (invertebrata) and in plants. Structurally, these compounds are identical with or close to the hormones of the molting and metamorphosis of arthropods and, to all appearance, play an important role in the plant-insect ecological system. More than 150 ecdysteroids isolated from plants are known.Ecdysteroids possess a high biological activity and a wide range of pharmacological effects [1]. An original tonic preparation 6kdisten, the active principle of which is ecdysterone, has been created in the Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, under the direction of N. K. Abubakirov. The study of the metabolism of ecdysteroids is arousing particular interest among chemists and biologists.A general scheme of the metabolism in the organism of animals has been given in the literature [2][3][4]. Information on the metabolism of ecdysteroids is also given in a review by Lafont et al. [3], in which, together with diverse metabolic transformations, a specificity of the reactions for a given type of animals is noted. In particular, on the administration of 1 mg of a-ecdysone or ecdysterone to white mice the excrements collected during the 48 h after administration contained a certain amount of the initial substance. A whole series of metabolites, with the absence of polar conjugates, was determined by the reversed-phase HPLC method. Subsequent normal-phase analysis showed the predominant presence of metabolkes not absorbing at 254 nm, which can be explained by the reduction of the keto group in ring B. In the review [3] it is stated that the structures of various metabolites have been determined with the aid of NMR and mass spectra. However, no concrete details are given.In view of this, we have studied the metabolism of ecdysterone in the organism of white rats. The qualitative chromatography of an ethyl acetate fraction of the urine revealed five substances of ecdysteroid nature. Three of them formed the main components of the total ecdysteroids.The IR spectra of metabolites (2)-(4) did not contain the absorption bands at 1640-1670 cm -I that are characteristic for a AT-6-keto group. The peak of the molecular ion had a very low intensity or was even absent because of the instability of the molecular ions of ecdysteroids on electron impact. In spite of the absence in the majority of electron-impact (EI) mass spectra of the peak of the M + ion, this method plays an important role...

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“…Amazingly, these compounds were detected in amounts comparable to or even higher than that of 20E, which strongly suggests that their metabolism and/or elimination is much slower. Based on the few available studies on the metabolism of ecdysone in mice 34 35 and of 20E in rodents 30 36 and in humans 33 37 , reduction at the B-ring is among the major metabolic routes of ecdysteroids. Moieties like a 5α-OH forming intramolecular H-bond with the 6-oxo group (polypodine B) or a conjugated 7(9,11)-dien-6-one (dacryhainansterone) might interfere with this process, and the lack of OH-25 (ajugasterone C and dacryhainansterone) can possibly decrease phase II metabolism i.e.…”

The metabolism of 20-hydroxyecdysone in mice: Relevance to pharmacological effects and gene switch applications of ecdysteroids

“…The metabolic fate of 20-hydroxyecdysone in mammals is still a matter of debate: Ramazanov et al [20] described metabolites of 20E in rat urine lacking the 6-oxo group and where the 7-ene was reduced. Tsitsimpikou et al [14] described dehydroxylated metabolites of 20E in humans (the removed -OH were tentatively assigned to positions 2 and 20).…”

“…More recent studies were performed on ingested 20E in rats [20] and humans [14], where the authors subsequently analyzed ecdysteroids in urine. Ramazanov et al [20] administered 20E to rats and they isolated unchanged 20E together with three metabolites, which were analyzed by IR and mass spectrometry, and concluded that there was a loss of the 6-keto group followed by the reduction of the 7-ene bond.…”

“…More recent studies were performed on ingested 20E in rats [20] and humans [14], where the authors subsequently analyzed ecdysteroids in urine. Ramazanov et al [20] administered 20E to rats and they isolated unchanged 20E together with three metabolites, which were analyzed by IR and mass spectrometry, and concluded that there was a loss of the 6-keto group followed by the reduction of the 7-ene bond. Tsitsimpikou et al [14] analyzed the urine of a human volunteer having ingested 20 mg of "Ecdysten TM " (a commercial preparation containing 20E); they collected urine and analyzed ecdysteroids by GC-MS after derivatization.…”

Preparation of novel bioactive semi-synthetic ecdysteroid derivatives

“…Besides unchanged 20E, three new metabolites were isolated. According to their observation, metabolic conversion resulted in the removal of the 7-en-6-one chromophore group, dehydroxylation at C-22 and epimerization at C-5 [34].…”